Melatonin mini-tablets and method of manufacturing the same

ABSTRACT

The instant invention is generally directed to a patient-friendly drug delivery system for targeted populations, such as pediatric and geriatric patients. Specifically, the present invention relates to a pharmaceutical composition in the form of mini-tablets. Even more specifically, the present invention relates to a pharmaceutical composition comprising a therapeutically-effective amount of melatonin in the form of mini-tablets.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of PCT/IB2016/057190, filed Nov. 29,2016, which claims the benefit of U.S. Provisional Application No.62/415,014 filed on Oct. 31, 2016, the disclosures of which areincorporated herein in their entirety by reference.

FIELD OF THE INVENTION

The present invention is generally directed to a patient-friendly drugdelivery system for targeted populations, such as pediatric andgeriatric patients.

BACKGROUND OF THE INVENTION

The goal of any drug delivery system is to provide a therapeutic amountof drug to the proper site in the body to achieve and then maintain thedesired drug concentration. The most convenient and commonly employedroute of drug delivery has historically been by solid oral dosage forms,particularly tablets and capsules. However, conventional tablets andcapsules are limited by their rigid dose content. Furthermore,difficulty swallowing tablets and capsules is a problem for manypatients, and can lead to a variety of adverse events and patientnoncompliance with treatment regimens.

Melatonin is an indole-derived hormone produced at night by the pinealgland, and it plays a major physiological role in the regulation ofsleep. Melatonin is produced and secreted into the plasma in a circadianrhythm which parallels the sleep-wake cycle. Exogenous melatonin isoften administered as a sleep-aid. Melatonin is also used to treatdependence on, tolerance of, or addiction to a benzodiazepine, asdescribed in U.S. Pat. No. 6,469,044, the disclosure of which isincorporated herein by reference in its entirety. Treatment withmelatonin has been shown to produce positive effects on sleep induction,sleep quality, and most importantly, day-time-functioning as well asquality of life. Melatonin use is not associated with development ofdependency.

Melatonin is available in several solid oral dosage forms, particularlytablets and capsules. Existing melatonin oral dosage forms includeimmediate-release dosage forms, useful for treating delayed sleep onset,and prolonged release forms, useful for sleep maintenance. Oralabsorption of melatonin is rapid and peak plasma levels are achieved 20to 60 min following ingestion.

Existing melatonin products suffer from disadvantages including poorpatient compliance issues due to difficulty in swallowing tablets, e.g.,prolonged-release Circadin® tablets, which are about 8.1 mm in diameterand 3-5 mm thick. Due to these difficulties, some patients break, crush,or chew the prolonged-release Circadin® tablets, which results in lossof its prolonged-release profile. As such, when Circadin® tablets arebroken, crushed or chewed, they exhibit a release profile that is closeto immediate-release melatonin.

There exists a need in the art for improved drug delivery systems foruse in patient populations having an inability to swallow tablets andcapsules, e.g., pediatric and geriatric populations. Specifically, thereexists a need in the art for novel mini-tablet formulations. Even morespecifically, there exists a need in the art for novel melatoninmini-tablet formulations having precise pharmacologic andpharmacokinetic properties.

BRIEF SUMMARY OF THE INVENTION

The present disclosure is generally directed to a patient-friendly drugdelivery form and system for patients that have difficulty swallowingmelatonin oral dosage forms intact.

In one embodiment, the present disclosure relates to a melatoninmini-tablet that contains a therapeutically effective amount ofmelatonin and one or more pharmaceutically acceptable carriers, whereinthe mini-tablet has a diameter of less than or equal to 4 mm.

Another embodiment of the invention relates to a method of manufacturinga melatonin mini-tablet, the method comprising combining atherapeutically effective amount of melatonin and one or morepharmaceutically acceptable carriers to produce a mixture, andcompressing the mixture into mini-tablets that each have a diameter ofless than or equal to 4mm.

The instant invention also relates to a method of inducing sleep in apatient in need thereof, the method comprising orally administering tothe patient a pharmaceutical mini-tablet comprising a therapeuticallyeffective amount of melatonin, wherein sleep is induced in the patient.Additionally, the invention relates to a method of orally administeringmelatonin to a patient who has difficulty swallowing tablets, the methodcomprising orally administering to the patient a pharmaceuticalmini-tablet comprising a therapeutically effective amount of melatonin.

The invention further relates to a pharmaceutical mini-tabletformulation comprising melatonin in combination with at least onepharmaceutical carrier, diluent or coating, wherein, upon administrationto a human, the formulation releases melatonin over time such that theperson's melatonin plasma profile substantially simulates the melatoninplasma profile of a human having a normal endogenous melatonin profile.

In certain embodiments, the invention further relates to apharmaceutical formulation containing a plurality of mini-tabletscontaining melatonin. In certain embodiments, the plurality ofmini-tablets in the pharmaceutical formulation is a combination ofimmediate release and controlled-release mini-tablets. In otherembodiments, each of the plurality of mini-tablets in the pharmaceuticalformulation is a controlled-release mini-tablet. In other embodiments,each of the plurality of mini-tablets in the pharmaceutical formulationis an immediate-release mini-tablet provided in the form of apharmaceutical formulation that has a controlled-release profile, e.g.,in a controlled release capsule.

Further embodiments of the invention comprise a method of inducing sleepin a patient in need thereof, the method comprising manufacturing amelatonin mini-tablet, and orally administering to the patient apharmaceutical mini-tablet comprising a therapeutically effective amountof melatonin.

These and other embodiments of the invention will be described infurther detail below.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a plot of endogenous melatonin plasma levels (adapted fromArendt et al, J Clin Endocrinol Metab. 1985; 60(6): 1166-73. 1985).

DETAILED DESCRIPTION OF THE INVENTION

Mini-tablets according to the present disclosure satisfy long-felt, butunmet therapeutic needs to provide effective melatonin therapy to apatient suffering from impaired swallowing and/or undergoingpolypharmacy therapy. A problem with existing melatonin oral dosage,either immediate-release dosage forms or prolonged-release dosage forms,is that they are difficult to swallow for some patients. As such,existing melatonin products suffer from disadvantages including patientcompliance issues due to difficulty in swallowing tablets, e.g.,prolonged-release Circadin® tablets, which are about 8.1 mm in diameterand 3-5 mm thick. Due to these difficulties, some patients break, crush,or chew the prolonged-release Circadin® tablets, which results in lossof its prolonged-release profile. As such, when Circadin® tablets arebroken, crushed or chewed, they exhibit a release profile that is closeto immediate-release melatonin. Due to these problems, before thepresent invention, there was a long-felt, but unmet need for aprolonged-release dosage form of melatonin with improved swallowing,flexible dosing, and better patient compliance. The present disclosuresatisfies the need in the field by providing melatonin mini-tabletshaving improved swallowing, flexible dosing, and better patientcompliance, as well as a controlled-release profile that achieves thesame minimal blood levels of melatonin present at night in the brain ofa human with a normal endogenous melatonin profile, shown in FIG. 1, aswell as an acceptable safety profile.

Mini-tablets according to the present disclosure provide pharmacokineticand pharmacodynamics properties such that a patient achieves a minimalblood level of about 60 to about 200 picograms melatonin per milliliterover at least four hours following the administration without sufferingunacceptable side effects. In certain embodiments, mini-tabletsaccording to the present disclosure provide pharmacokinetic andpharmacodynamics properties such that a patient achieves a minimal bloodlevel of about 100 to about 200 picograms melatonin per milliliter overat least four hours following the melatonin administration withoutsuffering unacceptable side effects.

In certain embodiments, the mini-tablets will release less than 50% ofthe active pharmaceutical ingredient within 1 hour of oraladministration. In certain embodiments, the mini-tablets will releaseabout greater than 70% of the active pharmaceutical ingredient within 6hours of oral administration.

Mini-tablets also offer therapeutic benefits such as dose flexibility.Mini-tablets are flat or slightly curved tablets with a diameter lessthan 4.0 mm. Mini-tablets are particularly suitable for polypharmacytherapy and dose-flexibility because they may be filled into a capsule,thereby allowing administration of specifically tailored dosage amountsor drug cocktails for personalized patient therapy. Mini-tabletsfacilitate the simultaneous administration of non-compatible drugs (i.e.drugs that can't otherwise be formulated together). Mini-tablets mayinclude immediate release, delayed release, and/or controlled releaseformulations. Due to increased surface area in relation to volume, adrug can be released more efficiently from mini-tablets compared totraditional tablets.

Mini-tablets are especially promising for use in pediatric populationsbecause a smaller tablet is more likely to be acceptable to children.Studies have found that mini-tablets are a potential dosage formsuitable for 2-6 year olds (based on placebo tablets 3 mm in diameter).(Thomson, S. A. et al., Pediatrics, 2009; 123: e235-e8.) Other studieshave found that very young children (6-12 months) were fully capable ofswallowing mini-tablets of 2 mm diameter and that they often preferredthem to sweet liquid formulations. (Spomer, N., et al., Arch. Dis.Child., 2012; 97:283-86.) As used herein, a “pediatric patient” or“pediatric subject” means a human between 2 and 18 years of age.

In an embodiment of the present invention, the mini-tablets include anactive pharmaceutical ingredient and one or more pharmaceuticallyacceptable carriers that are formulated so as to providecontrolled-release of the active pharmaceutical ingredient according toa desired pharmacokinetic and pharmacodynamics profile. As used herein,the term “mini-tablet” means a flat or slightly curved pharmaceuticaltablet having a diameter ranging between about 1.0 and 4.0 mm.

According to an embodiment of the present invention, the mini-tabletscontain melatonin as an active ingredient. The melatonin may be presentin a therapeutically effective amount, from about 1.0% to about 20.0% byweight of the total weight of the mini-tablet. In certain embodiments,the therapeutically effective amount of the active pharmaceuticalingredient in each mini-tablet is about 1 to about 10 mg, e.g., 1 mg, 2mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg or 10 mg. Melatonin analogswhich substantially imitate the function of melatonin in the human bodycan be used in place of melatonin in the formulations and methods of thepresent invention. Such analogs include ramelteon, agomelatine,tasimelteon, β-methyl-6-chloromalatonin and TK-301. Other acceptableanalogs are known to persons of skill in the art and include thoselisted in Depreux et al., J. Med. Chem. 37:3231-3239 (1994).

According to an embodiment of the present invention, the mini-tabletsmay contain one or more pharmaceutically acceptable carriers. Suitablecarriers include, for example, diluents, lubricants, binders, glidants,anti-adherents, and other excipients. Suitable carriers include lactose,calcium hydrogen phosphate and acrylic resin carriers such as thoseproduced under the name EUDRAGIT® by Rohm Pharmaceuticals in Darmstadt,Germany. In addition to the above ingredients, pharmaceutical grademagnesium stearate/stearic acid as a glidant, talc as an anti-adherentand colloidal silica as a lubricant may be included in the mini-tablet.The mini-tablets of according to the present disclosure may also containone or more of ammonio methacrylate copolymer, calcium hydrogenphosphate dihydrate, lactose monohydrate. The ammonio methacrylatecopolymer may be ammonio methacrylate copolymer type A (U.S.Pharmacopeia #1029909) or ammonio methacrylate copolymer type B (U.S.Pharmacopeia #1029910) or any other polymer providing the desiredcontrolled release profile. In some embodiments, the mini-tabletsaccording to the present invention include a fast dissolving sugar oralcohol that is not lactose, e.g., mannitol, sorbitol, erythritol,xylitol, dextrose, sucrose.

In some embodiments, the ratio between melatonin, ammonio methacrylatecopolymer, calcium hydrogen phosphate dihydrate, and lactose monohydratein the mini-tablet may be 1:1.1-5.9:0.8-8.3:1.8-8.8 by weight. In otherembodiments, the ratio between melatonin, ammonio methacrylatecopolymer, calcium hydrogen phosphate dihydrate, and lactose monohydratein the mini-tablet may be 1:1.175:0.85:1.865. In further embodiments,the ratio between melatonin, ammonio methacrylate copolymer, calciumhydrogen phosphate dihydrate and lactose monohydrate in the mini-tabletmay be 1:5.88:8.25:8.75 by weight.

The drug-release profile is strongly affected by formulation parametersand may be measured by in vitro dissolution of melatonin frommini-tablets in distilled water at 37° C. The type and amount ofrelease-controlling agent (usually polymer) used in mini-tabletssimilarly determines the drug-release patterns mainly by diffusion. Theinstant inventors found that, in matrix mini-tablet studies, increasingthe amount of rate-controlling compound led to slower drug release,which may be due to the increased hydrophobicity of the system. It wasdiscovered that increasing water-insoluble compounds (e.g., lactose)provides faster drug release due to their water solubility and drugdiffusion promotion.

Mini-tablet production is similar to the production of standard tablets,but requires excellent powder flow due to the small dies. Mini-tabletproduction also requires exact control of process parameters and specialcaution during tablet press assembly in order to avoid tool damage. Thepresent inventors discovered that it was not possible to use knowninformation about Circadin® tablets to make a priori assumptions orpredictions about the resultant flowability, dissolution and releasecharacteristics of mini-tablet formulations. In addition, the presentinventors discovered that it was not possible to use known informationabout a developed mini-tablet dosage form, e.g., the first melatoninmini-tablet, to make a priori assumptions or predictions about theresultant flowability, dissolution and release characteristics of amini-tablet having a different dosage amount, e.g., a secondmini-tablet.

The mini-tablets of the instant invention may be provided as compressedtablets. The compressed mini-tablets may be prepared using the processof direct compression. In the direct compression method of tabletproduction, dry ingredients are thoroughly mixed and then compressedinto tablets. The process of direct compression is convenient andcost-effective. However, the process is highly influenced by thecharacteristics of the active pharmaceutical ingredient (API) as well asthe excipients, including flowability, compressibility andcompatibility. Excipients must be selected carefully, because the rawmaterials must demonstrate good flowability and compaction propertiesfor successful operation. Good powder flowability is necessary in termsof providing uniform die filling and for production of mini tablets withacceptable weight and content uniformity.

In order to improve flowability of the API/excipients powder, drygranulation via slugging or roller compaction can be employed. Drygranulation is used for increasing the bulk density of powders, whilstincreasing the particle size, resulting in better flowing material,which is a prerequisite for manufacturing tablets on high speedproduction equipment. Bonding the particles of various substancestogether during the compaction process reduces the tendency forsegregation of powder particles of different substances. This results inan improvement of the homogeneity of the active ingredients (API) withinthe powder blend, causing an improvement of dose uniformity of suchdosage forms.

In some embodiments, the mini-tablets are coated. The type of coatingprocess used usually depends on the type of coating material to beapplied, whereas the durability of the tablet core depends both on thecoating material and application process. Generally, one of thefollowing types of coating procedures are used in the pharmaceuticalindustry: sugar coating, film coating, compression coating, and entericcoating.

The mini-tablets of the instant invention may be provided as apharmaceutical controlled-release formulation comprising melatonin incombination with at least one pharmaceutical carrier, diluent orcoating, wherein, upon administration to a patient, the formulationreleases melatonin over time such that the patient's melatonin plasmaprofile substantially simulates the melatonin plasma profile of a humanhaving a normal endogenous melatonin profile.

The mini-tablet may be administered to a patient who has troublesleeping, or who suffers from a melatonin deficiency or distortion incomparison to a person with a normal endogenous plasma melatoninprofile. The patient may be, for example, a pediatric patient, ageriatric patient, a disabled patient, a patient who has an autismspectrum disorder, a patient who has a neurogenetic disease, or apatient who has been diagnosed with dysphagia (difficulty swallowing).

As used herein, a “geriatric patient” or “geriatric subject” means ahuman of greater than 65 years of age.

A melatonin mini-tablet of the instant invention can be administered toa patient, for example, once or twice daily at preselected times, inorder to raise the level of melatonin in the patient's blood to adesired level. In a preferred embodiment, the melatonin mini-tablet isadministered so that the amount of melatonin in the patient's blood willsubstantially simulate the normal plasma melatonin night time profile,as shown in FIG. 1. Preferably, the mini-tablet will be administeredbefore sleep, so that the desired profile will be achieved while thepatient sleeps. Optionally, the melatonin mini-tablet may beadministered between a first sleep period, such as before bedtime, and asecond sleep period, such as during a period of waking in the middle ofthe night. In some embodiments, a first mini-tablet may be administeredbefore a first sleep period, and a second mini-tablet may beadministered between the first sleep period and a second sleep period.The first mini-tablet and the second mini-tablet may contain differentamounts of melatonin.

In other embodiments the melatonin mini-tablet may be administeredseveral hours before the desired bedtime to reset the biological clockin subjects suffering from transient or chronic circadian rhythmsdisorders (for example jet lag following trans meridian flight, sleepfollowing night shift, clock resetting in totally blind individuals withnon-24 h sleep wake disorder, delayed sleep phase syndrome).

In certain embodiments, melatonin mini-tablets are administered incombination with a substance which alters the phase position or shape ofthe patient's melatonin plasma profile, such as a melatonin receptormodifier or a melatonin profile modifier. As melatonin is known to actat a specific time of day and be ineffective at other times of the daydue to diurnal variations in melatonin receptors, it is important thatmelatonin and its receptors be present simultaneously. Melatoninreceptor modifiers include short-acting benzodiazepines, such asoxazepam and triazolam; melatonin profile modifiers includebenzodiazepines, such as alprazolam (McIntyre, et al., ChronobiologyInternational, 10:205-213 [1993]), beta-blockers, such as propranolol(Brismar et al., Acta Medica Scandinavia, 223:525 [1988]), serotoninuptake inhibitors, such as desipramine (Franey et al., British J. Med.Pharmacol., 22:73 [1986]), acetylcholesterase inhibitors (Wong, C. W.,Drugs Aging, 33(7):451-60 [2016]), and alpha antagonists, such asclonidine (Lewy et al., J. Pharmaceutics and Pharmacology, 38:55[1986]).

In certain embodiments, the melatonin mini-tablets can be administeredin combination with light therapy. Light can be used to adjust apatient's biological clock. In addition, a patient who has insufficientexposure to light may have internal desynchronization of his bodilyrhythms, which may result in melatonin being produced during the daytimerather than at night. In such cases, treatment only with melatonin willnot be fully satisfactory, as the patient also will have melatonin inhis blood during the daytime. Light is known to suppress melatoninproduction by the pineal gland, so in these circumstances light can beused to help blunt melatonin production during the day. Exposure tolight during the daytime can be continued until the patient's biologicalclock stabilizes. Thus, in accordance with the present invention, itwould be desirable to encourage exposure to light during the day andavoidance of light at night.

Various Embodiments of the Invention Comprise

1. A controlled-release melatonin mini-tablet comprising: atherapeutically effective amount of melatonin; and one or morepharmaceutically acceptable carriers; wherein the mini-tablet has adiameter of less than or equal to 4 mm and has a release profile of lessthan 50% melatonin release within 1 hour, and about greater than 70%melatonin release within 6 hours.

1. The controlled-release melatonin mini-tablet of embodiment 1, whereinthe therapeutically effective amount of melatonin is 1 mg.

3. The controlled-release melatonin mini-tablet of embodiment 1, whereinthe therapeutically effective amount of melatonin is 2 mg.

4. The controlled-release melatonin mini-tablet of embodiment 1, whereinthe therapeutically effective amount of melatonin is 3 mg.

5. The controlled-release melatonin mini-tablet of embodiment 1, whereinthe therapeutically effective amount of melatonin is 4 mg.

6. The controlled-release melatonin mini-tablet of embodiment 1, whereinthe therapeutically effective amount of melatonin is 5 mg.

7. The controlled-release melatonin mini-tablet of any of embodiments 1to 6, wherein the mini-tablet is formulated such that it produces aminimal blood level of about 60 to about 200 picograms melatonin permilliliter over at least four hours after oral ingestion of thecontrolled-release melatonin mini-tablet by a human patient.

8. The controlled-release melatonin mini-tablet of any of embodiments 1to 7, wherein the mini-tablet is formulated such that it produces aminimal blood level of about 100 to about 200 picograms melatonin permilliliter over at least four hours after oral ingestion of thecontrolled-release melatonin mini-tablet by a human patient.

9. The controlled-release melatonin mini-tablet of any of embodiments 1to 8, wherein the mini-tablet contains one or more of the ammoniomethacrylate copolymer, calcium hydrogen phosphate dihydrate, lactosemonohydrate.

10. The controlled-release melatonin mini-tablet of any of embodiment 9,wherein the ammonio methacrylate copolymer is ammonio methacrylatecopolymer type A.

11. The controlled-release melatonin mini-tablet of embodiment 9,wherein the ammonio methacrylate copolymer is ammonio methacrylatecopolymer type B.

12. The controlled-release melatonin mini-tablet of any of embodiments9, 10 and 11, wherein the ratio between melatonin, amino methacrylatecopolymer, calcium hydrogen phosphate dihydrate and lactose monohydrateby weight is 1:1.1-5.9:0.8-8.3:1.8-8.8.

13. The controlled-release melatonin mini-tablet of any of embodiments 1to 12, wherein the mini-tablet comprises a fast dissolving sugar oralcohol that is not lactose.

14. The controlled-release melatonin mini-tablet of any of embodiments 1to 32, wherein the mini-tablet is coated with a pharmaceuticallyacceptable coating.

15. A method of manufacturing a controlled-release melatoninmini-tablet, the method comprising: combining a therapeuticallyeffective amount of melatonin and one or more pharmaceuticallyacceptable carriers to produce a mixture; and compressing the mixtureinto mini-tablets that each have a diameter of less than or equal to 4mm such that the mini-tablet has a controlled-release profile of lessthan 50% melatonin released within 1 hour of dissolution, and aboutgreater than 70% melatonin released within 6 hours of dissolution.

16. The method of embodiment 15, further comprising a step of coatingthe tablets with a pharmaceutically acceptable coating.

17. The method of embodiment 15 or 16, wherein the combining stepcomprises dry blending the therapeutically effective amount of melatoninand the one or more pharmaceutically acceptable carriers.

18. The method of any of embodiments 15, 16, or 17, wherein the one ormore pharmaceutically acceptable carriers comprise a fast dissolvingsugar or alcohol that is not lactose.

19. The method of any of embodiments 15 to 18, wherein thepharmaceutically acceptable carriers comprise one or more of calciumhydrogen phosphate dihydrate, ammonio methacrylate copolymer, andlactose monohydrate.

20. A method of inducing sleep in a patient in need thereof, the methodcomprising: orally administering the controlled-release mini-tablet ofembodiment 1 to the patient; wherein sleep is induced in the patient.

21. The method of embodiment 20, wherein the patient is a pediatricpatient.

22. The method of embodiment 20, wherein the patient is a geriatricpatient.

23. The method of any of embodiments 20 to 22, wherein thetherapeutically effective amount is 1 mg.

24. The method of any of embodiments 20 to 22, wherein thetherapeutically effective amount is 2 mg.

25. The method of any of embodiments 20 to 22, wherein thetherapeutically effective amount is 3 mg.

26. The method of any of embodiments 20 to 22, wherein thetherapeutically effective amount is 4 mg.

27. The method of any of embodiments 20 to 22, wherein thetherapeutically effective amount is 5 mg.

28. The method of any of embodiments 20 to 27, wherein the mini-tabletcomprises one or more of the calcium hydrogen phosphate dihydrate,ammonio methacrylate copolymer, and lactose monohydrate.

29. The method of any of embodiments 20 to 28, wherein the tablet isadministered before sleep.

30. The method of any of embodiments 20 to 29, wherein the tablet isadministered between a first sleep period and a second sleep period.

31. A method of orally administering melatonin to a patient who hasdifficulty swallowing tablets, the method comprising: orallyadministering the controlled-release mini-tablet of embodiment 1 to thepatient.

32. The method of embodiment 31, wherein the therapeutically effectiveamount is 1 mg.

33. The method of embodiment 31, wherein the therapeutically effectiveamount is 2 mg.

34. The method of embodiment 31, wherein the therapeutically effectiveamount is 3 mg.

35. The method of embodiment 31, wherein the therapeutically effectiveamount is 4 mg.

36. The method of embodiment 31, wherein the therapeutically effectiveamount is 5 mg.

37. The method of any of embodiments 31 to 36, wherein the mini-tabletcomprises one or more of the calcium hydrogen phosphate dihydrate,ammonio methacrylate copolymer and lactose monohydrate.

38. A method of inducing a phase shift of the circadian rhythm of apatient in need thereof, the method comprising: orally administering thecontrolled-release mini-tablet of embodiment 1 to the patient; wherein aphase shift in the patient's circadian rhythm is induced in the patient.

39. A method of safely inducing and maintaining sleep in a patient inneed thereof, the method comprising: providing a pharmaceutical productcomprising one or more melatonin mini-tablets capable of inducing sleepin a patient and achieving a minimal blood level of about 60 to about200 picograms melatonin per milliliter over at least four hoursfollowing the administration without inducing unacceptable side effectsin a human, wherein said pharmaceutical product is manufactured bycombining a therapeutically effective amount of melatonin and one ormore pharmaceutically acceptable carriers to produce a mixture,compressing the mixture into one or more mini-tablets that each have adiameter of less than or equal to 4 mm such that the mini-tablet has arelease profile of less than 50% melatonin release within 1 hour, andabout greater than 70% melatonin release within 6 hours, and optionallyfilling a plurality of the mini-tablets into a capsule; and orallyadministering the one or more mini-tablets to the patient.

40. A pharmaceutical mini-tablet formulation comprising melatonin incombination with at least one pharmaceutical carrier, diluent orcoating, wherein, upon administration to a patient, the mini-tabletformulation releases melatonin over time such that the patient'smelatonin plasma profile substantially simulates the melatonin plasmaprofile of a human having a normal endogenous melatonin profile.

41. Use of a controlled-release melatonin mini-tablet for therapy, thecontrolled-release melatonin mini-tablet comprising a therapeuticallyeffective amount of melatonin; and one or more pharmaceuticallyacceptable carriers; wherein the mini-tablet has a diameter of less thanor equal to 4 mm and has a release profile of less than 50% melatoninrelease within 1 hour, and about greater than 70% melatonin releasewithin 6 hours.

42. Use of a controlled-release melatonin mini-tablet in a method ofinducing sleep in a patient in need thereof, the controlled-releasemelatonin mini-tablet comprising a therapeutically effective amount ofmelatonin; and one or more pharmaceutically acceptable carriers; whereinthe mini-tablet has a diameter of less than or equal to 4 mm and has arelease profile of less than 50% melatonin release within 1 hour, andabout greater than 70% melatonin release within 6 hours.

43. Use of a controlled-release melatonin mini-tablet in a method ofinducing a phase shift of the circadian rhythm of a patient in needthereof, the controlled-release melatonin mini-tablet comprising atherapeutically effective amount of melatonin; and one or morepharmaceutically acceptable carriers; wherein the mini-tablet has adiameter of less than or equal to 4 mm and has a release profile of lessthan 50% melatonin release within 1 hour, and about greater than 70%melatonin release within 6 hours.

44. Use of a controlled-release melatonin mini-tablet in a method ofsafely inducing and maintaining sleep in a patient in need thereof, thecontrolled-release melatonin mini-tablet comprising a therapeuticallyeffective amount of melatonin; and one or more pharmaceuticallyacceptable carriers; wherein the mini-tablet has a diameter of less thanor equal to 4 mm and has a release profile of less than 50% melatoninrelease within 1 hour, and about greater than 70% melatonin releasewithin 6 hours.

The present invention is illustrated by the following examples, whichare not intended to be limiting.

EXAMPLES Example 1 Development of a First Melatonin Mini-Tablet

The inventors sought to develop a first melatonin mini-tablet. 2 mgcontrolled-release melatonin tablets (about 8 mm diameter) werecommercially available under the brand name Circadin®, and the inventorsinitially attempted to use the formulation of Circadin® to develop thefirst melatonin mini-tablets. The commercial Circadin® formulationcontains a specific combination of ammonio methacrylate copolymer typeB, calcium hydrogen phosphate dihydrate, and lactose monohydrate. Theformulation of Circadin® is described in U.S. Pat. No. 6,469,044, whichis incorporated herein by reference in its entirety. The 2 mg Circadin®formulation is also shown in Table I, below.

The inventors initially attempted to prepare a melatonin mini tablet bydirect compression using the same inactive ingredients as those used incommercial Circadin® 2 mg. However, it was impossible to use theCircadin® formulation to produce a melatonin mini-tablet because anunacceptable difference in melatonin release rate was recognized.Specifically, decreasing the tablet size from the standard level (8 mm)to mini-level (≤4 mm) resulted in unacceptably fast drug release due toincreased surface-to-volume ratio. Additionally, the Circadin® tabletwas produced using wet granulation, and required the use of an organicsolvent as a granulation liquid, causing health, safety, disposition andresidual level issues. Accordingly, it was necessary to develop acompletely novel formulation and manufacturing process in order toproduce mini-tablets that could achieve the same pharmacokinetic andpharmacodynamic properties as the Circadin® tablet.

Various formulations for the melatonin mini-tablet were produced by dryblending. Initially, the tablets were formulated with decreased ratiosof lactose monohydrate and an increased ratio of calcium hydrogenphosphate dihydrate when compared to Circadin® 2 mg. These mini-tabletsdemonstrated promising dissolution profiles, but were still outside theCircadin® 2 mg dissolution specification.

In subsequent studies, two additional lots were prepared using anincreased amount of calcium hydrogen phosphate (55.5% by weight), and12% or 15% by weight of ammonio methacrylate copolymer type B,respectively. These variations were made in an attempt to slow down thedissolution profile of the first melatonin formulation. Mini-tabletscontaining 35% lactose and about 33% of calcium hydrogen phosphate gaveoptimal results with a dissolution profile falling between the low andhigh limit dissolution specifications. Table I shows the ratio ofingredients (by weight) in the first melatonin mini-tablet formulation,in comparison to the Circadin® formulation.

TABLE I Calcium Ammonio Hydrogen Methacrylate Phosphate Copolymer, TypeMelatonin Dihydrate B or A Lactose First Minitab 1 8.25 5.87 8.75 2 mgCircadin 1 20 20 40

Example 2 Development of a Second Melatonin Mini-Tablet

In order to produce an acceptable second melatonin mini-tablet, it wasnecessary to design, manufacture and test at least 10 differentformulations. The initial formulations were based on the firstmini-tablet formulation shown in Table I. Table II presents sevendifferent tablet formulations (Ex. 1-Ex. 7), for which the proportionsof calcium hydrogen phosphate dihydrate, ammonio methacrylate copolymer,and lactose monohydrate were varied in order to obtain adequate physicalmini-tablet properties, and to obtain acceptable dissolution profiles.

For the first formulation (Ex. 1), the increased amount of melatonin wascompensated for by reducing the amount of calcium hydrogen phosphate.However, the compressed tablets revealed a dissolution profile which wastoo slow compared to the target profile.

Lactose monohydrate is a fast-release agent. Based on the assumptionthat the hydrophilic lactose will increase the dissolution rate, asecond prototype (Ex. 2) was manufactured with an increased amount oflactose. In order to compensate for the increased lactose, the amount ofammonio methacrylate copolymer type B was decreased, while calciumhydrogen phosphate was kept the same as the first prototype. Thedissolution profile of tablets of the second prototype was surprisinglytoo slow.

After the confirmation that higher lactose in the second prototypeincreased the dissolution rate, the third prototype (Ex. 3) wasmanufactured with a maximum amount of lactose. To compensate for theincreased amount of lactose, the amount of ammonio methacrylatecopolymer type B and calcium hydrogen phosphate was reduced. Testing ofthis third prototype revealed that the dissolution profile of the meanvalues complied with the target dissolution profile of the firstmini-tablet formulation. However, there was an unacceptably highvariability among the tested samples (8 tabs).

Assuming that the high variability of the third prototype was due toincomplete matrix formation, the fourth prototype (Ex. 4) was preparedwith an increased amount of ammonio methacrylate copolymer type B. Thisincrease was compensated for by a decrease in calcium hydrogenphosphate. Testing of this fourth prototype showed that the meandissolution rate was unacceptably slow and did not meet the targetspecifications.

In an attempt to get a formulation with a faster dissolution rate, afifth prototype (Ex. 5) was manufactured. While the componentcombinations were similar to the second formulation, a different qualityof lactose, having a smaller particle size, was used. Testing the fifthprototype revealed that the particle size of lactose did not influencethe dissolution of melatonin. Accordingly, it was necessary to designand test further prototypes. Sixth and seventh prototypes (Ex. 6 and Ex.7) were manufactured using a more permeable grade of ammoniomethacrylate copolymer (type A). The sixth and seventh prototypes werebased on the first and second prototypes, respectively. The dissolutionprofiles of the sixth and seventh prototypes were acceptable.

TABLE II Ex. 1 Ex. 2 Ex 3 Ex. 4 Ex. 5 Ex. 6 Ex. 7 Melatonin 1 1 1 1 1 11 Type of B B B B B A A Ammonium Methacrylate Ammonio 1.17 0.78 0.6 0.80.8 1.18 0.78 Methacrylate Calcium 0.85 0.85 0.6 0.4 0.4 0.85 0.85Hydrogen Phosphate Lactose 1.75 2.15 2.58 2.58 2.58 1.75 2.15Monohydrate

Example 3 Human Clinical Trial

The effect of prolonged-release (PR) melatonin mini-tablets according tothe present invention was determined in a study population consisting ofrandomized 125 Children with Autism Spectrum Disorder (ASD) and/orneurogenetic diseases. The children were screened and entered a 4 weekssleep hygiene period, those who did not respond to thenon-pharmacological treatment continued into a single blind placeborun-in for 2 weeks; those who were still eligible after these 2 weeks,were randomized to receive either 2 mg active treatment (2× 1 mg PRmelatonin mini-tablet) or placebo for 3 weeks. After these 3 weeks thosewho did not respond to the treatment were escalated to a dose of 5 mg(5× 1 mg PR melatonin mini-tablet) in both treatment groups for another10 weeks double blind period (altogether 13 weeks double blind treatmentperiod). After this period, children continued for a 13 week open labelperiod on the dose that they took up to that point.

Sleep parameters were measured by a Daily Sleep and Nap Diary that wascompleted by the parents 2 weeks before each visit. For each subject,the mean sleep variable was calculated as the mean of the last 14 daysprior to each scheduled visit; the change from baseline in mean variablewas analyzed using a mixed-effects model for repeated-measures (MMRM).

It was found that the PR melatonin mini-tablet significantly improvedtotal sleep time over placebo after 3 months (SE=standard error) asshown in Table III.

TABLE III Adjusted treatment mean sleep variable (SE) PR Treatmentmelatonin mini- Placebo difference tablets (N = 58) (N = 61) (SE)p-value Week 15 56.16 (10.46) 18.73 (10.82) 32.43 (15.10) 0.034

It was also found that PR melatonin MT significantly improved sleepinitiation (SL) over placebo after 3 months as shown in Table IV.

TABLE IV Adjusted treatment mean sleep initiation (SE) PR Treatmentmelatonin mini- Placebo difference tablets (N = 58) (N = 61) (SE)p-value Week 15 −37.88 (6.82) −12.58 (7.00) −25.30 (9.79) 0.011

Conclusion: PR melatonin mini-tablets treatment improves sleep in ASDchildren suffering from sleep disturbances by shortening sleepinitiation and improving sleep maintenance.

All citations (e.g., scientific journal publications, patents, and otherreference material) mentioned herein are hereby incorporated herein byreference to the same extent as if each individual citation wasspecifically and individually indicated to be incorporated by reference.

While particular embodiments of the invention have been particularlydescribed hereinabove, it will be appreciated that the present inventionis not limited thereto, since as will be readily apparent to skilledpersons, many modifications or variations can be made. Suchmodifications or variations which have not been detailed herein aredeemed to be obvious equivalents of the present invention.

The foregoing summary, description, examples and drawings of theinvention are not intended to be limiting, but are only exemplary of theinventive features which are defined in the claims.

1. A controlled-release melatonin mini-tablet comprising: atherapeutically effective amount of melatonin; and one or morepharmaceutically acceptable carriers; wherein the mini-tablet has adiameter of less than or equal to 4 mm and has a release profile of lessthan 50% melatonin release within 1 hour, and about greater than 70%melatonin release within 6 hours.
 2. The controlled-release melatoninmini-tablet of claim 1, wherein the therapeutically effective amount ofmelatonin is 1 mg, 2 mg, 3 mg, 4 mg, or 5 mg.
 3. The controlled-releasemelatonin mini-tablet of claim 1, wherein the mini-tablet is formulatedsuch that it produces a minimal blood level of about 60 to about 200picograms melatonin per milliliter or about 100 to about 200 picogramsmelatonin per milliliter over at least four hours after oral ingestionof the controlled-release melatonin mini-tablet by a human patient. 4.The controlled-release melatonin mini-tablet of claim 1, wherein themini-tablet contains one or more of ammonio methacrylate copolymer,calcium hydrogen phosphate dihydrate, lactose monohydrate.
 5. Thecontrolled-release melatonin mini-tablet of claim 4, wherein the ammoniomethacrylate copolymer is ammonio methacrylate copolymer type A.
 6. Thecontrolled-release melatonin mini-tablet of claim 4, wherein the ammoniomethacrylate copolymer is ammonio methacrylate copolymer type B.
 7. Thecontrolled-release melatonin mini-tablet of claim 4, wherein the ratiobetween melatonin, ammonio methacrylate copolymer, calcium hydrogenphosphate dihydrate and lactose monohydrate by weight is1:1.1-5.9:0.8-8.3:1.8-8.8.
 8. The controlled-release melatoninmini-tablet of claim 1, wherein the mini-tablet comprises a fastdissolving sugar or alcohol that is not lactose.
 9. Thecontrolled-release melatonin mini-tablet of claim 1, wherein themini-tablet is coated with a pharmaceutically acceptable coating.
 10. Amethod of manufacturing a controlled-release melatonin mini-tablet, themethod comprising: combining a therapeutically effective amount ofmelatonin and one or more pharmaceutically acceptable carriers toproduce a mixture; and compressing the mixture into mini-tablets thateach have a diameter of less than or equal to 4 mm such that themini-tablet has a controlled-release profile of less than 50% melatoninreleased within 1 hour of dissolution, and about greater than 70%melatonin released within 6 hours of dissolution.
 11. The method ofclaim 10, further comprising a step of coating the tablets with apharmaceutically acceptable coating.
 12. The method of claim 10, whereinthe combining step comprises dry blending the therapeutically effectiveamount of melatonin and the one or more pharmaceutically acceptablecarriers.
 13. The method of claim 10, wherein the one or morepharmaceutically acceptable carriers comprise a fast dissolving sugar oralcohol that is not lactose.
 14. The method of claim 10, wherein thepharmaceutically acceptable carriers comprise one or more of calciumhydrogen phosphate dihydrate, ammonio methacrylate copolymer, andlactose monohydrate.
 15. The method of claim 14, wherein the ratiobetween melatonin, ammonio methacrylate copolymer, calcium hydrogenphosphate dihydrate and lactose monohydrate by weight is1:1.1-5.9:0.8-8.3:1.8-8.8.
 16. A method of inducing sleep in a patientin need thereof, the method comprising: orally administering thecontrolled-release mini-tablet of claim 1 to the patient, wherein sleepis induced in the patient.
 17. The method of claim 16, wherein thepatient is a pediatric patient.
 18. The method of claim 16, wherein thepatient is a geriatric patient.
 19. The method of claim 16, wherein thetherapeutically effective amount is 1 mg, 2 mg, 3 mg, 4 mg, or 5 mg. 20.The method of claim 16, wherein the mini-tablet comprises one or more ofcalcium hydrogen phosphate dihydrate, ammonio methacrylate copolymer,and lactose monohydrate.
 21. The method of claim 16, wherein themini-tablet is administered before sleep.
 22. The method of claim 16,wherein the mini-tablet is administered between a first sleep period anda second sleep period.
 23. The method of claim 20, wherein the ratiobetween melatonin, ammonio methacrylate copolymer, calcium hydrogenphosphate dihydrate and lactose monohydrate by weight is1:1.1-5.9:0.8-8.3:1.8-8.8.
 24. A method of orally administeringmelatonin to a patient who has difficulty swallowing tablets orcapsules, the method comprising orally administering thecontrolled-release mini-tablet of claim 1 to the patient.
 25. The methodof claim 24, wherein the therapeutically effective amount is 1 mg, 2 mg,3 mg, 4 mg, or 5 mg.
 26. The method of claim 24, wherein the mini-tabletcomprises one or more of calcium hydrogen phosphate dihydrate, ammoniomethacrylate copolymer and lactose monohydrate.
 27. A method of inducinga phase shift of the circadian rhythm of a patient in need thereof, themethod comprising: orally administering the controlled-releasemini-tablet of claim 1 to the patient, wherein a phase shift in thepatient's circadian rhythm is induced.
 28. A method of safely inducingand maintaining sleep in a patient in need thereof, the methodcomprising: providing a pharmaceutical product comprising one or moremelatonin mini-tablets capable of inducing sleep in a patient andachieving a minimal blood level of about 60 to about 200 picogramsmelatonin per milliliter over at least four hours following theadministration without inducing unacceptable side effects in a human,wherein said pharmaceutical product is manufactured by combining atherapeutically effective amount of melatonin and one or morepharmaceutically acceptable carriers to produce a mixture, compressingthe mixture into one or more mini-tablets that each have a diameter ofless than or equal to 4 mm such that the mini-tablet has a releaseprofile of less than 50% melatonin release within 1 hour, and aboutgreater than 70% melatonin release within 6 hours, and optionallyfilling a plurality of the mini-tablets into a capsule; and orallyadministering the one or more mini-tablets to the patient.
 29. Apharmaceutical mini-tablet formulation comprising melatonin incombination with at least one pharmaceutical carrier, diluent orcoating, wherein, upon administration to a patient, the mini-tabletformulation releases melatonin over time such that the patient'smelatonin plasma profile substantially simulates the melatonin plasmaprofile of a human having a normal endogenous melatonin profile.